Polycystic Ovary Syndrome in Adolescent Girls Dalinda A

Polycystic Ovary Syndrome in Adolescent Girls Dalinda A. Condino, MD Chief, Division of Adolescent Medicine Associate Professor of Clinical Pediatrics UBMD-Pediatrics

Disclosure �I have no relevant financial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in this CME activity. �I intend to discuss off-label use of medication (metformin, oral contraceptive pills) in the context of standard PCOS treatment.

Objectives �Understand the epidemiology and diagnostic criteria for PCOS �Recognize the clinical spectrum and pathophysiology of androgen excess in adolescents �Develop a management strategy for a PCOSaffected adolescent

Case 1 NW is an 18 year old female who presents for ‘fertility concerns. ’ She has had irregular periods since menarche. Her primary care provider prescribed birth control pills 3 yrs ago for contraception which she has not been taking. She is now concerned because she has not yet conceived after being off the pill for months. Her boyfriend of two years is ready to have children. On ROS she reports that she visits the salon weekly for hair removal, denies significant problems with acne, has an elevated cholesterol, and no other health problems. On exam she is well developed, Tanner V female with a BMI of 35, with AN, some pustules on her back, FG of 10, but exam is otherwise unremarkable.

Case 2 ST is a 19 year old female who presents to student health for a routine exam. She reports that she has not had a period in more than six months. She is an athlete who runs indoor and outdoor track and has been doing so since about the age of 15 years. She has also been a dancer since age 6 and prior to doing track danced semi-professionally. She was evaluated by her PMD for this and told that she wasn’t having periods because she was “too athletic and thin. ” FH and other PMH are non-contributory. She reports having a healthy diet and not limiting herself at all. She eats meals with her team and coaches who encourage lots of complex carbohydrates at mealtimes. She is an honor student, never been sexually active, but is dating. She has normal vitals, a BMI of 20, Tanner V breasts and pubic hair, and no other significant findings.

They Both Have PCOS! �Obesity & classic features vs. Lean, healthy girl �Difference = 10 years between their diagnoses and initiation of treatment

Polycystic Ovary Syndrome �Common reproductive endocrine disorder 5 -10% of women of reproductive age Strong family history/evidence of genetic basis Studies of first degree relatives of PCOS patients 24% mothers 32% sisters � First described by Stein & Leventhal (1935) Seven women with amenorrhea, infertility, enlarged ovaries Follow report added hirsutism to observations Wedge resections (1930 s) Hormonal management (1970 s/80 s) Stein IF, Leventhal NL Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol, 1935; 29: 181– 191

Cost of PCOS The total cost of evaluating and providing care to reproductive-aged PCOS women in the United States Initial Evaluation $93 Million (2. 1%) Treating menstrual dysfunction (hormonal $1. 35 Billion (31%) Providing infertility care $533 Milion (12. 2%) PCOS-related diabetes $1. 77 Billion (40. 5%) Treating Hirsutism $622 Million (14. 2%) Total $ 4. 36 Billion Azziz R, Marin C, Hoq L, Badamgarav E, Song P, Health Care-Related Economic Burden of the Polycystic Ovary Syndrome during the Reproductive Life Span, The Journal of Clinical Endocrinology & Metabolism, 2005; 90(8): 4650– 4658

Quality of Life p 68. 6 Healthy Comparisons 76. 3 -7. 7 . 04 91. 2 94. 8 -4. 1 . 001 77. 2 81. 8 -6. 0 . 029 93. 9 94. 8 -2. 9 . 04 Mental Health 66. 5 70. 3 -3. 8 . 065 Change in Health/Yr 2. 5 . 26 . 04 Subscale PCOS General Health Perception Physical Functioning Family Activities Behavior 2. 8 Trent M, et. al. , Arch Ped Adol Med, 2002; 156: 1 -5 .

Where does it all start? �Peri-menarchal period �Abnormal physiological transition to puberty LH secretion Adrenal androgen production Body mass Insulin resistance �Area of active research the cause is still unknown Focus �Lutenizing hormone stimulation ovary �Gn. RH secretion / gene expression �Insulin involvement in androgen production

Clinical Features �Menstrual Dysfunction Amenorrhea Oligomenorrhea Anovulation or oligoovulation Infertility Dysfunctional Uterine Bleeding Endometrial Hyperplasia

Hyperandrogenism �Hirsutism (Ferriman-Gallwey Score > 8)1 �Acne (Global Acne Score)2 �Male pattern baldness/alopecia �One or more elevated androgens: Testosterone (T), Free Testosterone, Dehydroepiandrosterone (DHEAS), Androstenedione 1) Ferriman D, Gallwey JD. Clinical assessment of body hair and growth in women J Clin Endocrinol Metab 1961; 121: 1440 , 2) Doshi A, Zaheer A, Stiller M. A comparison of current acne grading systems and proposal of a novel system. (Reproduced with permission in: Emans SJ, et. al. Pediatric and Adolescent Gynecology, Lippincott, Williams, & Wilkins, 5 th Ed, 205, p 305 -307

Ferriman Gallwey Score

Diagnostic Criteria Clinical Findings NIH Androgen Excess Required Menstrual abnormality Required Rotterdam, 2003 2 of 3 Required Androgen Excess Society, 2006/2009* Required 1 of 2 Required PCO on ultrasound ACOG Practice Bulletin, 2009, 114 (4): 936 -949, Azziz R. et. al. Fertil Steril, 2009, 91 (2): 456

Clitoromegaly Normal clitoral width<5 mm Courtesy of Dr. Jean Emans, Adolescent Medicine Program, Boston Children’s Hospital

Ovarian Pathology �Classic Morphology: thickened, white capsule enlarged ovary with multiple small cysts at least 10 follicles, 2 -8 mm in diameter �Non-specificity: PCO in 92% women with idiopathic hirsutism 87% with oligomenorrhea 26% with amenorrhea 23% with reported regular cycles

Classic Ovarian Morphology “String of Pearls” Courtesy of Dr. Jean Emans, Adolescent Medicine Program, Boston Children’s Hospital

Hyperinsulinemia �PCOS pts: increased hyperinsulinemia and insulin resistance �Clinical finding: Acanthosis Nigricans/Obesity �Insulin: augments ovarian androgen response to LH �Cytochrome 450 c 17 alpha enzyme activity increased �Involvement of IGFs �Clinical improvement after Metformin Nestler et. al, NEJM 1996, 333: 617 -623

Differential Diagnosis �PCOS �Idiopathic Hirsutism �Late-Onset CAH �Drugs: steroids, anticonvulsants �Cushing syndrome/disease �Ovarian or adrenal tumors

History �Virilization: deepening of the voice, temporal recession, increased muscle mass, clitoromegaly �Hirsutism (time course, distribution) �Acne �Menstrual History �Acanthosis Nigricans �History of premature adrenarche �Family History

Physical Examination �Height, weight, vital signs �Ferriman-Gallwey Score �Acanthosis nigricans �Acne �Male pattern balding �Upper body muscle mass �Galactorrhea �Clitoromegaly �Ovarian masses

Laboratory Studies �Goals: To rule out adrenal or ovarian tumor To assess severity of androgen excess To evaluate source of hyperandrogenism �Ovarian ( Free and total testosterone) �Adrenal (DHEA-S) �Additional supportive labs : LH FSH (Rule Out Ovarian Failure) 17 -OHP (Early AM) Lipid profile Fasting Glucose/2 hour OGTT

Source of Androgen Interpretation of Labs Adrenal Cortex Ovary Peripheral Conversion of Precursors Testosterone ~25% ~50% Androstendione 50% --- DHEA 90% 10% --- DHEA-S 100% --- Emans SJ, et. al. Pediatric and adolescent gynecology, 5 th ed. Philadelphia: Lippincott, Williams, Wilkins; 2005: 301

PCOS Treatment Options

Treatment Goals �Hormonal suppression to lower ovarian androgen levels �Improve menstrual irregularity �Prevent endometrial hyperplasia �Improve clinical findings affecting appearance (hirsutism and acne) �Increase insulin sensitivity �Prevent long-term complications

Oral Contraceptives and PCOS �Decrease LH levels and decrease androgen synthesis �Increase SHBG levels, increase T binding, and decrease free T �Inhibit 5 alpha-reductase which decreases conversion of T to DHT (active androgen) �Treat early

Progestin Only Therapy • Regulates menses • Lessens risk of endometrial cancer • Medroxyprogesterone 10 mg for 12 -14 days every 1 -3 months • Progestin only pills may not achieve menstrual regulation

Managing Hirsutism & Acne Courtesy of Dr. Jean Emans, Adolescent Medicine Program, Boston Children’s Hospital

Temporary Methods Method Action Side Effects Bleaching 6% peroxide bleaches hair Irritation, ineffective, allergic reactions, syncope if persulfate used Shaving Mechanical cutting of hair Quick growth, stubble, irritation Chemical Depilatory Dissolves hair shaft by reduction of disulfide bonds Irritation, allergic/contact dermatitis, strong odor Tweezing Extraction of hair shaft Pain, hyperpigmentaton, scar, folliculitis Waxing Uniform extraction of hair Thermal burns, allergic/contact dermatitis, folliculitis, irritation, scarring

“Permanent” Methods Method Action Comments Electrolysis Low flow current causes chemical reaction destroying hair follicle Slow (1 minute per hair) Thermolysis High frequency current destroys hair follicle Faster (seconds per hair) Laser light targets melanin in follicle causing thermal injury Thermal injury restricted to follicle Treatment of large areas with fewer side effects Traditional techniques cause significant side effects on darker skin

Laser • Nd: Yag felt to be safest Deeper penetration Less absorption by epidermal melanin • Newer Technique using longer-wavelength diode laser light effective in darker skinned patients • Requires multiple visits to dermatologist • Expensive Battle EF, Soden CE. Use of Lasers in Darker Skin Types, Seminars on Cutaneous Medicine and Surgery, 2009; 28: 130 -140

Potential Laser Side Effects Courtesy: Dr. Eliot F. Battle, Jr , Cultura Cosmetic Dermatology & Laser Center/ Department of Dermatology Howard University Hospital, Washington, DC

Laser Hair Removal: Safe and Highly Effective 2 years after last treatment Courtesy: Dr. Eliot F. Battle, Jr , Cultura Cosmetic Dermatology & Laser Center/Howard University Hospital, Washington, DC

Improvement in Skin Tone/Texture 40 ms 30 J/cm 2 1 year after 12 Treatments Courtesy: Dr. Eliot F. Battle, Jr , Cultura Cosmetic Dermatology & Laser Center/Howard University Hospital, Washington, DC

Hormonal Treatment of Hirsutism • Oral contraceptives Estrogens increase SHBG, decreasing free T Suppress gonadotropin dependent ovarian androgens Suppress adrenal androgens Cyclic versus continuous pills (QD or 84 days and 7 days off) Patches and Rings �Limited research/clinical use documented in literature �Theoretically should be considered for treatment �Adherence

Hirsutism • Anti-androgens (e. g. spironolactone) to reduce hair diameter (41% at 12 months) best used with OCPs 50 -100 mg bid • Potential Side-effects: hypotension, lethargy, urinary frequency, hyperkalemia, nausea O’Brien RC, Cooper ME, Murray RM, et. al. Comparison of the sequential cyproterone acetate/estrogen vs. spironolactone /oral contraceptive in the treatment of hirsutism, J Clin Endocrinol Metab 1991; 72: 1008. **

What about OCPs with Drosperinone? �Observational study of women with PCOS � Determine if clinical and biochemical features of PCOS are ameliorated by Yasmin™ � 17 patients treated x 6 months � Results: 76% good cycle control no change in BMI increased insulin/triglycerides decreased testosterone/increased SHBG no change in hirsutism clinically � The anti-androgen contained in Yasmin ™ is just percentage of the spironolactone prescribed for PCOS Palen-Singh M, et. al. An observational study of Yasmin in the management of women with polycystic ovary syndrome. Fam Plann Reprod Health Care. 2004 Jul; 30(3): 163 -5.

Hirsutism • Gn. RH analogues Estrogen addback needed to preserve bone density • Prednisone for late onset CAH (21 OH deficiency) Treatment with OCs appears to be equally effective

Topical: Eflornithine 13. 9% Cream • Irreversible inhibitor of ornithine decarboxylase, an enzyme which mediates cell division and growth in hair follicles • Side-effects: burning, folliculitis (more likely if applied to shaved skin) �Need to continue mechanical hair removal methods �If discontinued hair growth will resume

Acne �Topical or oral medications depending on the type of acne �Oral contraceptive pills reduce the free and total testosterone improving acne

Acanthosis Nigricans �Treatment guided by its cause �Weight loss and treatment of underlying disorders �Topical: retinoic acid, corticosteroids, keratolytics �Oral: isotretinoin, ketoconazole

Insulin Resistance and Obesity • Weight loss if obese Reduces peripheral estrogen production Reduces cardiovascular risk Reduces insulin resistance and suppresses ovarian androgen production �Methods Exercise Decreased Caloric Intake Dietary modification Medications �Metformin �Orlistat Tang T, et. al. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized placebo-controlled, double blind multicentre study, Human Reproduction, 2006; 21 (1): 80 -89 Jayapogopal V, et. al. Orlistat is as beneficial as metformin in the treatment of polycystic ovary syndrome, J Clin Endocrinol Metab, 2005; 729 -733.

Insulin Sensitizing Agents • Metformin decreases androgens, decreased weight slightly resumption of menses in 68 -96% ovulation in 30 -40%, ? effect on hirsutism Dosing: � 500 mg TID � 850 mg BID �Extended Release (multiple formulations 500 mg, then increase to 1 -2 g /day for most formulations) side-effects - GI (flatulence, diarrhea)

Glucose Intolerance �Study of 254 women with PCOS, 0 and 2 hr post 75 gm glucose: 31% impaired glucose tolerance 7. 5% diabetes �In non-obese women: 10. 3% IGT and 1. 5% diabetes �Fasting glucose poor predictor of IGT Legro, J Clin Metab Endo 1999

Glucose Intolerance in Adolescents with PCOS � Study of 27 adolescents with PCOS � 8/27 had IGT; 1/27 type 2 DM � Fasting blood glucose abnormal in 2/8 � Glucose/Insulin ratio <4. 5 in 15/18 Palmert J Clin Endo Metab, 2002

Risk of Progression to Diabetes � 6. 2 year follow-up � Normal Glucose tolerance test at baseline 5/54 (9%) developed IGT 4/54 (8%) DM �BMI at baseline significant predictor of later adverse glucose tolerance Norman, Human Reproduction, 2001

Treatment �Manage urgent clinical needs �Treat PCOS and all comorbidities �Encourage lifestyle changes (nutrition and exercise) �Metformin Glycemic control Improves insulin resistance Improves reproductive function

Case 3 � JS is a 15 year old who presents with classic findings of PCOS: menstrual irregularity, clinical evidence of androgen excess (hirsutism & acne), and morbid obesity with signs of insulin resistance. Basic labs were obtained, but due to a lab error, liver function tests obtained instead of androgens. � Labs: AST: 94, ALT: 97 ALK 124 Chol 226 Glucose 110 TSH 1. 72, T 4 1. 3, Insulin 156 �Repeat labs show elevated androgens, repeat glucose NL, Repeat LFTS AST 139, ALT 176, Negative screening for infectious hepatitis �Diagnosis? What do you do now?

Additional Labs �Ultrasound: Liver is large and shows echogenicity consistent with fatty infiltrate. No evidence of biliary obstruction. Large spleen, Kidneys nl. Pancreas not seen. �Referred to GI �Patient non-adherent to recommendations for GI follow-up, dietary change, metformin. �Later developed type 2 DM �Eventually went to GI appointment: Liver biopsy consistent with steatohepatitis

Non-Alcoholic Fatty Liver Disease (NAFLD)& Steatohepatitis (NASH) � NAFLD Inflammation NASH � Associated with metabolic syndrome Obesity Hypertension Increased cholesterol Insulin resistance �Treatment No standard medical treatment Avoidance of toxic substances (ETOH, Medications) Weight Management Diabetes control Cholesterol control �Caution with statins, but research promising Zamor Curr Opin Cardiol. 2011 Jul; 26(4): 338 -412011; Bugianesi, E. Am J Gastroenterology, 2005, 100: 1082 NIDDK Information sheet: http: //digestive. niddk. nih. gov/ddiseases/pubs/nash/ (last accessed 11/15/11)

Case 4 � JE is a 17 year old female with a history of PCOS. Patient returns to clinic for routine gynecologic & PCOS care. Patient has lost 20 lbs in the last 6 months through diet and exercise. She is doing well in school, got great SAT scores, and has selected six colleges. She has been on OCPs for 2 years. Now, she reports becoming sexually active with one partner for 3 months, but has stopped using contraception (including condoms). When you ask her about this she says, “We’ll I can’t get pregnant so why bother? ”

Issues �PCOS patients can be oligo-ovulatory, not just anovulatory �Improvement in clinical status (weight loss, use of metformin) in an overweight patient can result in improvement in reproductive function ovulation �Studies have shown that non-contraceptive use is likely to occur among girls who perceive fertility impairment �She is at risk for sexually transmitted infections and pregnancy Development of recurrent STIs or PID would only complicate her fertility picture . Rainey DY, et. al. Self-perception of infertility among female adolescents. Am J Dis Child 1993; 147: 11053– 6

Fertility Concerns Adjusted OR=3. 4 95% CI: 1. 9 -6. 2 (p<. 001) Trent M, et. al, Fertility Concerns and Sexual Behavior in Adolescent Girls with Polycystic Ovary Syndrome: Implications for Quality of Life, Journal of Pediatric and Adolescent Gynecology, 2003; 16 (1): 33 -7

Fertility Concerns � 21% of PCOS patients expresses fertility concerns in spontaneous comments “Sometimes I’m worried about this disease because it makes me think about if I would have problems in the future with having babies. ” “I’m not sure how this affects me in the long run. Is it something that can hurt me? (i. e. Not being able to have kids, more susceptible to other diseases, etc. )” “It really did nothing to my life, the only thing I think is that I am afraid I will never be able to have children. ”

Sexual Risk Behaviors in Adolescents with PCOS Sexually Active (Ever) Age at First Intercourse Among Sexually Active Girls Adjusted OR: 2. 8 95% CI 1. 4, 5. 4 • No difference between age of initiation of sexual intercourse between groups • PCOS = 15. 7( 1. 5) years • Comparisons = 15. 7 ( 1. 8) years (p=0. 003) Trent M, Rich M, Austin SB, Gordon C. Fertility Concerns and Sexual Behavior in Adolescent Girls with Polycystic Ovary Syndrome: Implications for Quality of Life, Journal of Pediatric and Adolescent Gynecology, 2003; 16 (1): 33 -7

Fertility Concerns • Common question by the • • • � adolescent’s parents and late adolescent girl Remain optimistic—many treatment alternatives & once pregnant outcomes similar to nonaffected women of similar clinical status* Avoid making specific recommendations regarding fertility treatment & focus on treating PCOS Encourage academic development and achievement as future orientation is essential Education to protect reproductive organs (e. g. STI prevention)

Infertility Therapies • Weight loss/exercise (If obese) • Metformin • Clomiphene citrate • Gonadotropin therapy • Invitro Fertilization • Surgical options

Summary � Optimal Medical Management � Identification/Treatment Co. Morbidities Obesity Diabetes NAFLD Hypertension � Extensive Ongoing Patient Education �www. youngwomenshealth. org & Risk reduction �Reproductive/Sexuality �Family planning �Sexual relationships/negotiation �Testing/Treatment for STIs Cosmetic �Aestheticians �Dermatology Mental Health Reproductive Endocrinology Fertility Routine Adolescent �STD/HIV � Referral for Services PCOS-Related � Support Groups PCOSsupport. org

QUESTIONS